Genomic clones cross-hybridizing with Ly-6A.2 cDNA were isolated and characterized for functional Ly-6-related genes. Two new Ly-6 genes, designated Ly-6F.1 and Ly-6G.1, were found to have high nucleotide homology (> or = 70%) and the characteristic four exon gene organization of Ly-6A/E and Ly-6C. By a PCR-based assay, Ly-6G.1 mRNA was readily found in bone marrow, whereas Ly-6F.1 mRNA was not detected in lymphoid tissues. Thus, Ly-6G.1 represents an additional Ly-6 gene with apparent selective expression in hematopoietic cells distinct from Ly-6A/E and Ly-6C. Using the available deduced protein sequence data for mature Ly-6 proteins, searches of the database uncovered an evolutionary relationship of Ly-6 proteins with neurotoxins isolated from snake venoms. The protein sequence conservation between the two groups was selective for, but not limited to, residues in neurotoxins that have been found to be important for their tertiary structures. From this relationship, we propose a neurotoxin-like structure for Ly-6 and Ly-6-related proteins, such as CD59.